Despite advances in modern medicine and science, the population of Europe is becoming increasingly susceptible to the potential dangers of bacterial infection. Once easily dealt with by antibiotics, severe bacterial infections are again increasing sharply in Europe due to their growing resistance to available antibiotics. These range from respiratory infections to gastrointestinal infections, dermatitis and a variety of systemic infections.

Researchers from the universities of Dundee and St Andrews in Scotland, the Karolinska Institutet in Sweden and two German-based SMEs (LIONEX and mfd Diagnostics GmbH) have, together with collaborators in Oxford, joined forces under the AEROPATH project to develop potential solutions to the superbug problem.

This ambitious research project funded under the European Union (EU)'s 7th Research Framework Programme (FP7) aims to promote the development of relevant antimicrobial drugs and new approaches for combating the superbugs and overcoming their resistance to treatment.

Around one tenth of infections acquired during a hospital stay are caused by Pseudomonas aeruginosa (P. aeruginosa). This free-living bacterium is most commonly found in soil and water and is an opportunistic pathogen that infects humans with compromised natural defences, particularly those in hospital.

These bacteria are tolerant to a wide variety of physical conditions, including temperature, and are resistant to high concentrations of salts and dyes, weak antiseptics and many commonly used antibiotics. They are also capable of acquiring resistance to many others, making treatment difficult.

The aim of AEROPATH has been to gain a better understanding of the biology of the 'Gram-negative' type of bacteria at a molecular level by using the P. aeruginosa bacterium as a model and looking for ways to weaken or interfere with the bacterium's ability to cause infection. The AEROPATH team are confident of their potential to underpin early-stage drug discovery for development of antibiotic drugs.

In one particularly successful area the groups in Dundee and Oxford made a significant breakthrough in understanding how resistance to antibiotics might be overcome by producing the first ever 3D molecular image of one key drug target, Penicillin Binding Protein 3 (PBP3) and showing how drugs bind to it. Having this accurate 3D model of PBP3 and knowing where molecules called inhibitors bind, gives a clear picture of the interactions that inhibit this drug target.

The research was made possible by using a machine called a synchrotron in which electrons are accelerated at close to the speed of light and manipulated by special magnets to give off very intense X-rays. These X-rays were then used to probe tiny PBP3 crystals through diffraction methods, enabling the researchers to determine the 3D structure of the protein.

Knowing the 3D structure of an antibiotic bound to its target protein reveals the molecular mechanism and shows how the drug works and how it could be modified to overcome resistance. The structures identified so far suggest that there could be scope to develop new drugs that work in combination with existing PBP3 inhibitors to make them more effective and able to overcome resistance. Now that the exact chemical structure of the protein has been identified, researchers can begin developing new inhibitors and therapies.

Achievements in the first three years of the AEROPATH project include computer-based 'druggability' assessment of over 5 000 targets resulting in the release of the AEROPATH 'target database', and the validation of 28 targets alongside the cloning of more than 100 genes of selected targets. The output greatly enriches the database on P. aeruginosa drug targets for follow up studies.

The AEROPATH coordinator Professor William Hunter, from the College of Life Sciences at Dundee commented: "Because these organisms are so tough, we need new ideas for drugs and the way to do that is to find new targets or apply modern technologies to exploit old targets. We can then search out new compounds that will hit either group of drug targets."

Project details

Participants: United Kingdom (Coordinator), Sweden, Germany

FP7 Proj. N° 223461

Total
costs: € 6 049 979

EU
contribution: € 4 591 463

Duration:
November 2008 - October 2012

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